ES2533678T3 - Procedure for the preparation of astaxanthin dimethyldisuccinate - Google Patents

Abstract

Process for the preparation of astaxanthin dimethyldisuccinate aII-E of formula I ** Formula ** comprising the process steps: a) reacting a C10 dialdehyde of formula II ** Formula ** in a double Wittig reaction with a salt of C15 phosphonium of formula III ** Formula ** in which X- is the anion of an organic or inorganic acid HX, in a solvent comprising dichloromethane, by adding a solution of an alkali metal or alkaline earth metal alcoholate M1OR1 or M2 (OR1) 2 in an alcohol R1OH as the base, in which M1 is equal to Li, Na, K or Rb, M2 is equal to Mg, Ca, Sr or Ba and R1 is equal to methyl, ethyl, n-propyl or iso-propyl, to give an astaxanthin of formula IV ** Formula ** in which the two newly formed double bonds are present in both the Z configuration and the E configuration, if necessary followed by an aqueous processing of the mixture of reaction for the separation of salts M1X or M2X2; b) separating the alcohol R1OH from the reaction mixture of the process step a) by repeated washing of the reaction mixture with water or by distillation separation of a solvent mixture containing dichloromethane and the alcohol R1OH, if necessary of drying the reaction mixture by separation of water by means of azeotropic distillation of dichloromethane and water; c) reacting the astaxanthin of formula IV, which is in the reaction mixture treated in the process step b), in dichloromethane by adding methyl succinoyl chloride of formula V ** Formula ** and an organic base containing nitrogen to give an astaxanthin dimethyldisuccinate of the formula; ** Formula ** d) aqueous process the reaction mixture of the process step c) for the separation of water soluble salts; e) exchanging dichloromethane solvent for an R2OH alcohol by separating the dichloromethane from the reaction mixture of the process step d) by distillation and adding the R2OH alcohol to the reaction mixture, R2 being equal to methyl, ethyl, n- propyl or i-propyl; f) thermally isomerize the astaxanthin dimethyldisuccinate of the formula prepared in the process step c) to give astaxanthin dimethyldisuccinate aII-E of formula I by heating the reaction mixture containing R2OH of the process step e) to at least 50 ° C, the reaction mixture having a water content of 10% to 90% by volume of water with respect to the total volume of the reaction mixture, and producing astaxanthin dimethyldisuccinate aII-E of formula I in crystalline form and isolating if necessary below.

Description

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DESCRIPTION

Procedure for the preparation of astaxanthin dimethyldisuccinate

The present invention relates to an improved process for the preparation of astaxanthin dimethyldisuccinate aII-E of formula I.

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Astaxanthin itself is a coveted dye that is used primarily as a feed additive for pigmentation of farmed salmon.

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A very effective process for the preparation of astaxanthin is the double Wittig olefination of the symmetric C10 dialdehyde of formula II with two equivalents of the corresponding C15 phosphonium salt of formula III as described among others in Helv. Chim. Minutes 64, 7, 2445 (1981).

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This reaction can be carried out, for example, in dichloromethane using methanolic sodium methylate solution as a base (see also WO 2007128574) or by heating the components of formulas II and III in 1,2-epoxybutane.

For the improvement of the storage stability of astaxanthin in fish feed, various diesters of astaxanthin are proposed in WO 03/066583, mentioning among others astaxanthin dimethyldisuccinate of formula I.

For the preparation of astaxanthin diesters, crystalline astaxanthin is reacted according to WO 03/066583 in an inert solvent with a carboxylic acid chloride or a carboxylic acid anhydride in the presence of an organic base (WO 03 / 066583, page 7, lines 3 to 20). In the esterification of astaxanthin with a free acid, the reaction is carried out in the presence of a dehydration reagent (WO 03/066583, page 7, lines 21 to 28). Astaxanthin dimethyldisuccinate of formula I was obtained according to example 5 in WO 03/066583 (page 13, lines 13 to 25) in a yield of 49.9% and a purity of 79.3%. By subsequent recrystallization from methylene chloride / methanol, the diester could be obtained in a purity of 98% (according to HPLC).

It is disadvantageous in this process that crystalline astaxanthin is used as the starting material for esterification. The preparation of crystalline astaxanthin as an intermediate for esterification means a considerable production expense for crystallization, filtration, washing, drying, filling, storage and dosing of the solid in the next step. Furthermore, with the crystallization of astaxanthin yield losses occur through the residual solubility of the product of value in the mother liquor.

The objective of the present invention was to improve the drawbacks of the known synthesis of astaxanthin dimethyldisuccinate of formula I. On the one hand the process for the preparation of astaxanthin dimethyldisuccinate of formula I should be simplified and on the other hand the yield and purity should be improved of astaxanthin dimethyldisuccinate of formula I.

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This objective is achieved by a process for the preparation of astaxanthin dimethyldisuccinate aII-E of formula I

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comprising the process steps: a) reacting a C10 dialdehyde of formula II

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in a double Wittig reaction with a C15 phosphonium salt of formula III

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in which X-is the anion of an organic or inorganic acid HX,

10 in a solvent comprising dichloromethane, by adding a solution of an alkali metal or alkaline earth metal alcoholate M1OR1 or M2 (OR1) 2 in an alcohol R1OH as a base, in which

M1 is equal to Li, Na, K or Rb, M2 is equal to Mg, Ca, Sr or Ba 15 and R1 is equal to methyl, ethyl, n-propyl or iso-propyl,

to give an astaxanthin of formula IV

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in which the two newly formed double bonds are found both in the Z configuration and in the E configuration 20, if necessary followed by an aqueous processing of the reaction mixture for the separation of the M1X salts

or M2X2;

b) separating the alcohol R1OH from the reaction mixture of the process step a) by repeated washing of the reaction mixture with water or by distillation separation of a mixture of solvents which

25 contains dichloromethane and R1OH alcohol, if necessary followed by drying the reaction mixture by separation of water by means of azeotropic distillation of dichloromethane and water;

c) reacting the astaxanthin of formula IV, which is in the reaction mixture treated in the process step b), in dichloromethane by adding methyl succinoyl chloride of formula V

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and an organic base containing nitrogen to give an astaxanthin dimethyldisuccinate of formula la;

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d) aqueous processing the reaction mixture of the process step c) for the separation of water soluble salts;

e) exchanging dichloromethane solvent for an R2OH alcohol by separating the dichloromethane from the reaction mixture of the process step d) by distillation and adding the R2OH alcohol to the reaction mixture, R2 being equal to methyl, ethyl, n -propyl or i-propyl;

f) thermally isomerize the dimethyldisuccinate of formula Ia prepared in the process step c) to obtain astaxanthin dimethyldisuccinate aII-E of formula I by heating the reaction mixture containing R2OH of the process step e) to at least 50 ° C , presenting the reaction mixture a

10 water content of 10% to 90% by volume of water with respect to the total volume of the reaction mixture, and the astaxanthin dimethyldisuccinate aII-E of formula I being produced in crystalline form and isolated as appropriate below.

In the process step a) of the process according to the invention, a C10 dialdehyde of formula II is reacted

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in a double Wittig reaction with a C15 phosphonium salt of formula III

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wherein X-is the anion of an organic or inorganic acid HX, such as for example hydrochloric acid, hydrobromic acid or hydroiodic acid, a sulfonic acid, such as methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid, or an acid trihaloacetic acid, such as trifluoroacetic acid or trichloroacetic acid,

in a solvent comprising dichloromethane, by adding a solution of an alkali metal alcoholate

or alkaline earth metal M1OR1 or M2 (OR1) 2, preferably of an alkali metal alcoholate M1OR1 in an alcohol R1OH as the base, in which

M1 is equal to Li, Na, K or Rb, preferably Li or Na, in particular Na, 25 M2 is equal to Mg, Ca, Sr or Ba, preferably Mg

R1 is equal to methyl, ethyl, n-propyl or iso-propyl, preferably methyl or ethyl, in particular methyl,

to give an astaxanthin of formula IV

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30 in which the two newly formed double bonds are found both in the Z configuration and in the E configuration, if necessary followed by a subsequent aqueous processing of the reaction mixture for the separation of the M1X or M2X2 salts.

Preferably, in the case of anion X, it is a chloride or bromide. In process step a) the C10 dialdehyde of formula II and the C15 phosphonium salt of formula III are preferably dissolved first in a solvent

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containing more than 90% by volume, especially preferably more than 95% by weight of dichloromethane with respect to the total volume of the solvent, in particular pure dichloromethane, that is dichloromethane with a purity of more than 99% by volume.

Subsequently, in the process step a), the compounds of formulas II and III are preferably condensed by adding a solution of sodium methanolate in methanol as a base to obtain the astaxanthin of formula IV.

In the astaxanthin of formula IV, the two newly formed double bonds are found in both the Z configuration and the E configuration. Predominantly, that is to say in more than 50%, the two double bonds formed again in the astaxanthin of formula IV have the configuration E, E. The proportion of the newly formed double bonds with Z configuration amounts to up to 25% in the mixture of the astaxanthin of formula IV.

Preferably, in the process step a) the reaction mixture is subjected to aqueous processing for the separation of the M1X or M2X2 salts.

After aqueous processing, a crude solution of astaxanthin of formula IV in dichloromethane is obtained as a reaction mixture, which is saturated in water and contains residues of the alcohol R 1 OH, in particular methanol.

In the process step b) of the process according to the invention, the alcohol R 1 OH is separated from the reaction mixture of the process step a) by repeated washing of the reaction mixture with water or by distillation separation of a mixture of solvents containing dichloromethane and R1OH alcohol, in particular by distillation separation of the solvent mixture containing dichloromethane and R1OH alcohol, if necessary followed by drying the reaction mixture by water separation by means of azeotropic dichloromethane distillation and water.

Preferably, the alcohol R 1 OH is separated, in particular methanol in the process step b) by repeated distillation, washing of the distillate with water and reconduction of the distillate washed in the crude astaxanthin solution.

In the case of methanol, methanol can be separated from the reaction mixture as described above discontinuously in several steps. In a technical process the separation of methanol from the reaction mixture is preferably carried out continuously, the methanol being separated from the reaction mixture by continuous washing of the dichloromethane distillate containing methanol with water in a mixing / decanter apparatus. In this respect, the organic lower phase is continuously redirected to the crude astaxanthin solution, until the crude astaxanthin solution is free of methanol.

Preferably, after performing the methanol separation, the crude saturated astaxanthin water solution is dried according to procedures known to the expert, preferably by azeotropic distillation (dichloromethane / water heteroazeotrope). This can be done by simple distillation or by recirculation of water by means of a correspondingly constructed water separator.

All distillation steps are preferably performed at normal pressure, however they can also be performed under partial vacuum. For practical reasons (condensation capacity of dichloromethane azeotropes), however, one does not work below 30 kPa.

In the process step c) of the process according to the invention, the astaxanthin of formula IV, which is in the reaction mixture treated in the process step b), is reacted in dichloromethane by the addition of methyl succinoyl chloride of the formula V

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and an organic base containing nitrogen to give an astaxanthin dimethyldisuccinate of formula la

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The crude dichloromethane solution of astaxanthin obtained in the process step b) free of R 1 OH, preferably also free of water, in particular free of methanol and water is reacted in itself.

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known with the methylsuccinoyl chloride of formula V in the presence of an organic base to give the astaxanthin dimethyldisuccinate of formula la. Water-free or R1OH-free means in this context a water content or an R1OH content in the reaction mixture of less than 0.2% by weight, preferably less than 0.1% by weight, in particular less than 0.075% by weight of water or R 1 OH with respect to the mass of the reaction mixture.

As the organic base, which contains nitrogen, for example, amines, such as primary, secondary or tertiary alkylamines or arylamines, or basic nitrogen-containing heteroatoms such as pyridine or pyridine derivatives can be used. Preferably, a trialkylamine such as, for example, triethylamine, pyridine or a dialkylaminopyridine such as, for example, 4-dimethylaminopyridine, is used as the basis. Especially preferably, in the process step c) the organic base containing nitrogen is pyridine or a pyridine derivative.

The molar ratio of astaxanthin: methylsuccinoyl chloride is in the range of 1: 2.0 -1: 3.0, preferably 1: 2.1 -1: 2.5. The base is used at least stoichiometrically with respect to the acid chloride, preferably however in an excess of 10-50% by mole, with respect to the methyl succinoyl chloride. The reaction temperature can be found from -10 ° C to the reflux temperature of the reaction mixture. The reaction is preferably carried out in the temperature range of 0 ° C to 25 ° C.

In the process step d) of the process according to the invention, the reaction mixture of the process step c) is processed aqueous for the separation of water soluble salts. In this respect, the hydrochlorides are separated from the organic base, which contains a large amount of nitrogen, as well as still existing M1X or M2X2 salts, produced in the process step a) of the reaction mixture containing dichloromethane.

In the process step e) of the process according to the invention, the dichloromethane solvent is exchanged for an R2OH alcohol by separation of the dichloromethane from the reaction mixture of the process step d) by distillation and addition of the R2OH alcohol to the reaction mixture, R2 being equal to methyl, ethyl, n-propyl or i-propyl, in particular equal to methyl.

Preferably, in the process step e) the alcohol R2OH is equal to methanol.

The solvent exchange can be carried out in stages, a certain amount of dichloromethane being distilled off and replaced by a certain amount of R2OH alcohol and this procedure is repeated until the dichloromethane has been separated in the desired amount, preferably completely. Alternatively, the dichloromethane separated by distillation can also be continuously replaced by the corresponding volume of the alcohol R2OH (isocoric process mode). The complete separation of dichloromethane means in the previous context that the residual dichloromethane content is less than 0.5% by weight, preferably less than 0.1% by weight, in particular less than 0.05% by weight of dichloromethane with respect to to the mass of the reaction mixture.

The solvent exchange is carried out in order to crystallize the astaxanthin dimethyldisuccinate of formula la and in particular the astaxanthin aII-E dimethyldisuccinate of formula I, which are very soluble in dichloromethane, in an R2OH alcohol, the triphenylphosphine oxide still remaining in solution existing from the process stage a) and being able to separate well from the crystalline product accordingly.

Preferably water is added to the R2OH alcohol, in particular methanol, the amount of water being selected such that triphenylphosphine oxide does not precipitate yet. In principle, the water may have been added, at least partially, already before the solvent exchange (process step e)) to the reaction mixture. For the simplest calculation and determination of the amount of water necessary for a desired water content, the water is not added until the exchange of dichloromethane solvents for the R2OH alcohol, in particular methanol, to the reaction mixture. Preferably a water content of 10% to 90% by volume is adjusted, especially preferably from 30% to 70% by volume, very especially preferably from 40% to 60% by weight, in particular from 45% to 55%. % by volume of water with respect to the total volume of the reaction mixture.

In the process step f) of the process according to the invention, the astaxanthin dimethyldisuccinate of the formula prepared in the process step c) isomerically isomerized by heating the reaction mixture containing R2OH of the process step e) to at least 50 ° C to give astaxanthin aII-E dimethyldisuccinate of formula I, the reaction mixture having a water content of 10% to 90% by weight, especially preferably 30% to 70% by volume, so very particularly preferred from 40% to 60% by volume, in particular from 45% to 55% by volume of water with respect to the total volume of the reaction mixture, and producing astaxanthin dimethyldisuccinate aII-E of formula I in crystalline form and isolating itself if necessary below.

The reaction mixture of the process step e) is preferably isomerized at a temperature between 80 ° C and 120 ° C, especially preferably between 90 ° C and 110 ° C. If the desired temperature is above the boiling point of the solvent or of the solvent mixture with atmospheric pressure,

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The reaction mixture is heated in a closed system that is suitable for the overpressure that is generated.

The thermal isomerization in aqueous methanol between 80 ° C and 120 ° C is preferably carried out in the process step f), especially preferably between 90 ° C and 110 ° C with pressure inherent in a closed apparatus.

The reaction mixture is usually thermally isomerized for 1 to 20 hours at a temperature between 80 ° C and 120 ° C. At lower temperatures this time may also be longer.

The water content defined in process step f) is preferably adjusted by adding water to the reaction mixture following process step e).

After thermal isomerization, the mixture is usually cooled to 0 ° C to 25 ° C, preferably 0 ° C to 12 ° C, and crystallized formula I astaxanthin aII-E dimethyldisuccinate can be isolated in high yield and purity by filtration.

The process according to the invention described above avoids the drawbacks of the two-stage process, in which first all astaxanthin E is isolated and this crystalline product is then reacted to give the astaxanthin dimethyldisuccinate aII-E of formula I Surprisingly it was shown that an astaxanthin of formula IV prepared from the dialdehyde C10 of formula II and the phosphonium salt of C15 of formula III should not be isolated in substance for the conversion to dimethyldisuccinate of astaxanthin of formula la, but that it can be reacted as crude solution in the presence of triphenylphosphine oxide and other impurities of the synthesis directly with methyl methylsuccininochloride of formula V (methyl 4-chloro-4-oxo-butyrate) to give astaxanthin dimethyldisuccinate of formula la, and from this can be obtained after thermal isomerization astaxanthin dimethyldisuccinate aII-E of formula I in high yield and purity in crystalline form

The invention is explained by the following example, which does not however limit the invention.

Example 1

The crude astaxanthin solution was prepared by reaction of II with III in dichloromethane using methanolic sodium methylate solution (see Helv. Chim. Acta 64, 7, 2445 (1981). The solution contains 4.56% by weight of astaxanthin (HPLC analysis) and 0.8% by weight of methanol (GC analysis) as well as 0.55% by weight of water (Karl-Fischer titration).

982 g of this solution were placed (corresponding to 75 mmol of astaxanthin). At normal pressure, 350 ml of solvent was distilled off through a Normag column head. The upper aqueous phase of the distillate was separated and the lower phase was washed with 175 g of water. The phases were separated and the lower organic phase was redirected to the bottom of distillation.

This procedure was repeated twice. Then 350 ml of solvent was distilled off at normal pressure. The remaining distillation residue no longer contained methanol. The water content was 0.051% by weight.

To the distillation residue, 21.36 g (270 mmol) of pyridine were added at 20 ° C. Then, 34.92 g (225.0 mmol) of methyl succinoyl chloride (4-chloro-4-methyl oxobutyrate) was added dropwise at 20 ° C in 30 min. The reaction mixture was subsequently stirred for 3 h at 20-25 ° C. The reaction mixture was then hydrolyzed by adding 100 ml of water. The aqueous phase was separated and the organic phase was washed twice with 100 ml of water in each case. The dichloromethane was then distilled off through a Normag column head. The distillate was replaced simultaneously with methanol (isocoric process mode), until the transition temperature of 65 ° C had been achieved. The mixture was mixed with 300 ml of water, subsequently stirred for 4 h at 100 ° C with inherent pressure, cooled to 10 ° C and stirred for 1 h at 10 ° C. The precipitated product was filtered off, washed twice with in each case 50 ml of cold methanol (10 ° C) and dried overnight in the oven under vacuum at 50 ° C to 1 kPa.

Final weight: 52.5 g of Ax-DMDS (84.9% with respect to astaxanthin in the crude solution) Mp: 115-117 ° C Purity: 94.6% (% HPLC surface)

Claims (6)

1. Procedure for the preparation of astaxanthin dimethyldisuccinate aII-E of formula I image 1 comprising the process steps: a) reacting a C10 dialdehyde of formula II image2 in a double Wittig reaction with a C15 phosphonium salt of formula III image3 in which X-is the anion of an organic or inorganic acid HX, 10 in a solvent comprising dichloromethane, by adding a solution of an alkali metal or alkaline earth metal alcoholate M1OR1 or M2 (OR1) 2 in an alcohol R1OH as a base, in which M1 is equal to Li, Na, K or Rb, M2 is equal to Mg, Ca, Sr or Ba 15 and R1 is equal to methyl, ethyl, n-propyl or iso-propyl, to give an astaxanthin of formula IV image4 in which the two new double bonds formed are present in both the Z configuration and the E configuration 20, if necessary followed by aqueous processing of the reaction mixture for the separation of the M1X salts or M2X2; b) separating the alcohol R1OH from the reaction mixture of the process step a) by repeated washing of the reaction mixture with water or by distillation separation of a mixture of solvents which 25 contains dichloromethane and R1OH alcohol, if necessary followed by drying the reaction mixture by separation of water by means of azeotropic distillation of dichloromethane and water; c) reacting the astaxanthin of formula IV, which is in the reaction mixture treated in the process step b), in dichloromethane by adding methyl succinoyl chloride of formula V image5 30 8 and an organic base containing nitrogen to give an astaxanthin dimethyldisuccinate of formula la; image6 d) aqueous processing the reaction mixture of the process step c) for the separation of water soluble salts; 5 e) exchanging dichloromethane solvent for an R2OH alcohol by separating the dichloromethane from the reaction mixture of the process step d) by distillation and adding the R2OH alcohol to the reaction mixture, R2 being equal to methyl, ethyl, n -propyl or i-propyl; f) thermally isomerizing the astaxanthin dimethyldisuccinate of the formula prepared in the process step c) to give astaxanthin dimethyldisuccinate aII-E of formula I by heating the 10 reaction mixture containing R2OH of the process step e) up to at least 50 ° C, the reaction mixture having a water content of 10% to 90% by volume of water with respect to the total volume of the reaction mixture, and producing the astaxanthin dimethyldisuccinate aII-E of formula I in crystalline form and being isolated as appropriate below.

2.

Process according to claim 1, wherein in the process step a) the base is a solution of sodium methanolate in methanol.

3. The method according to claim 2, wherein in the process step b) the methanol is separated from the reaction mixture by continuous washing of the dichloromethane distillate containing methanol with water in a mixing / decanter apparatus.

Four.

Process according to one of claims 1 to 3, wherein in the process step c) the organic base containing nitrogen is pyridine or a pyridine derivative.

5.

Process according to one of claims 1 to 4, wherein in the process step e) the alcohol R2OH is equal to methanol.

6.

Process according to claim 5, wherein in the process step f) thermal isomerization is carried out in aqueous methanol between 80 ° C and 120 ° C with pressure inherent in a closed apparatus.

Method according to one of claims 1 to 6, in which the water content defined in the process step f) is adjusted by adding water to the reaction mixture following the process step e). 9